20 - World Journal of Gastroenterology

in alcoholic liver steatosis [39,40] . Generally, alcohol intake
increases gut permeabilization, which allows an increased
uptake of endotoxin/lipopolysaccharide (LPS) in portal
circulation [18] . Kupffer cells are then activated in response
to LPS via TLR4 signaling cascade, leading to the production
of several types of pro-inflammatory mediators such
as TNF-α, IL-1, IL-6, and ROS [3,4,39] . Of these mediators,
the increased expression of TNF-α and enhanced
activity of its receptor (TNF-α R1) have been observed
in alcoholic liver steatosis in mice [39-42] . In addition, it has
been reported that TNF-α has the potential to increase
mRNA expression of SREBP-1c, a potent transcription
factor of fat synthesis, in the liver of mice and to stimulate
the maturation of SREBP-1 in human hepatocytes [43,44] .
Furthermore, a recent report demonstrated that alcoholmediated
infiltration of macrophages decreased the
amount of adiponectin (known as anti-steatosis peptide
hormone) production of adipocytes, leading to alcoholic
liver steatosis [45] . Therefore, Kupffer cells/macrophages
might contribute to the development of alcoholic liver
steatosis via the upregulation of the SREBP1 activity in
hepatocytes and the downregulation of the production
of adiponectin in adipocytes. In contrast, IL-6 produced
by Kupffer cells/macrophages is a positive regulator in
protecting against alcoholic liver steatosis via activation of
signal transducer and activator of transcription (STAT)3,
consequently inhibiting of SREBP1 gene expression in
hepatocytes [46-48] .
Endocannabinoids, endogenous cannabinoids, are lipid
mediators that interact with cannabinoid receptors (CB1
and CB2) to produce effects similar to those of marijuana
[49] . There are the two main endocannabinoids, arachidonoyl
ethanolamide (anandamide) and 2-arachidonoylglycerol
(2-AG). Recently, an intriguing report suggested that
alcoholic liver steatosis is mediated mainly through HSCderived
endocannabinoid and its hepatocytic receptor [8] .
The study suggested that chronic alcohol consumption
stimulated HSC to produce 2-AG, and the interaction with
the CB1 receptor upregulated the expression of lipogenic
genes SREPB1c and fatty acid synthase but downregulated
the activities of AMPK and carnitine palmitoyltransferase
1. Consequently fat is accumulated in the hepatocyte. More
recently, a related study reported that the increased expression
of CB1 receptors on hepatocytes because of alcohol
consumption was mediated by RA acting via a RA receptor
(RAR)-γ [27] . This study also showed that 2-AG treatment
in mouse hepatocytes increased the production of RA by
Raldh1, the catalytic enzyme of retinaldehyde into RA. RA
then binds with RAR-γ, increasing the expression of CB1
receptor mRNA and protein, and consequently exacerbating
the alcohol-mediated fat accumulation via enhanced
endocannabinoid and lipogenic signaling pathways [27] .
Reports stating that alcohol consumption simultaneously
elevated the expression of RAR and the production of
retinol metabolites, including RA, in mouse and rat liver,
supported these findings [50-52] . Moreover, hepatocytes and
HSCs are major sources of retinoids, including retinol and
RA, in the body [26,53] . In contrast to the CB1 receptors, the
association of CB2 receptors with the development of
WJG|www.wjgnet.com
Suh YG et al . HSCs and innate immunity in liver disease
EtOH
+
AMPK
+
CPT1
+
Fatty acid
β-oxidation
-
HSC
2-AG+
CB1 R+
-
Lipid/fat
accumulation
Figure 1 Regulatory mechanisms of the hepatic lipogenesis and CB1 receptor
expression via hepatic stellate cell-derived endocannabinoids/CB1
receptors and retinoic acid/retinoic acid receptor-γ in hepatocytes, respectively.
CB1 R: CB1 receptor; AMPK: AMP-activated protein kinase; HSC:
Hepatic stellate cell; 2-AG: 2-arachidonoylglycerol; SREBP-1: Sterol regulatory
element-binding protein-1; FAS: Fatty acid synthase; RA: Retinoic acid; RAR:
Retinoic acid receptor.
hepatic steatosis has not yet been studied in depth. One
study showed that the expression of CB2 receptors was
increased in the livers of patients with non-alcoholic fatty
liver disease [54] . In an animal model, however, feeding of
high-fat diet for 15 wk induced severe fatty liver in wildtype
mice, but not in hepatic CB2 knockout mice [55] . The
involvement of endocannabinoid, RA, and their receptors
has been integrated in Figure 1.
Interestingly, in contrast with previous reports that
endocannabinoids activated HSCs to induce liver fibrosis
and alcoholic liver steatosis [8,56] , Siegmund et al reported
that HSCs’ sensitivity to anandamide (AEA)-induced cell
death was because of low expression of fatty acid amide
hydrolase and that 2-AG also induced apoptotic death
of HSCs via ROS induction [57-59] . These data indicated
that endocannabinoids might play negative roles in liver
fibrosis. Therefore, the functions of endocannabinoids to
HSCs are still unclear and need to be studied further.
ALCOHOLIC STEATOHEPATITIS BY
INNATE IMMUNITY AND HSCS
+
Raldh1
RARγ
CB1 R promoter
Alcoholic steatohepatitis has a mixed status with fat accumulation
and inflammation in the liver, which has the potential
to progress into more severe pathologic states such
as alcoholic liver fibrosis, cirrhosis, and hepatocellular
carcinoma. In response to alcohol uptake, many hepatic
cells participate in the pathogenesis of alcoholic steatohepatitis.
However, as described above, mainly Kupffer
cells and HSCs initiate and maintain hepatic inflammation
and steatosis [4,8,60-63] . Considering their specific location at
the interface between the portal and systemic circulation,
Kupffer cells are the central players in orchestrating the
immune response against endotoxin (LPS) via TLR4 signaling
pathways [62,64] . TLR4 initiates two main pathways,
and when TLR4 binds LPS, TIR domain-containing adaptor
protein and myeloid differentiation factor 88 (MyD88)
are recruited, resulting in the early-phase activation of nu-
2545 May 28, 2011|Volume 17|Issue 20|
+
SREBP-1
FAS
+
Hepatocyte
RA
2-AG+
CB1 R